The successful elimination of pathogens, neoplastic cells, or self-reactive immune mechanisms following prophylactic or therapeutic immunization depends to a large extent on the ability of the host's immune system to become activated in response to immunization and to mount an effective response, preferably with minimal injury to healthy tissue.
The rational design of vaccines initially involves identification of immunological correlates of protection—the immune effector mechanism(s) responsible for protection against disease—and the subsequent selection of an antigen that is able to elicit the desired immune response. Once this appropriate antigen has been identified, it is essential to deliver it effectively to the host's immune system.
New vaccines are presently under development and in testing for the control of various neoplastic, autoimmune and infectious diseases. In contrast to older vaccines which were typically based on live-attenuated or non-replicating inactivated pathogens, modern vaccines are composed of synthetic, recombinant, or highly purified subunit antigens. Subunit vaccines are designed to include only the antigens required for protective immunization and are believed to be safer than whole-inactivated or live-attenuated vaccines. However, the purity of the subunit antigens and the absence of the self-adjuvanting immunomodulatory components associated with attenuated or killed vaccines often result in weaker immunogenicity.
For example, DNA vaccination is a novel and potentially powerful approach to prevent and treat disease. The advantages of plasmid DNA immunization, as compared to the traditional protein vaccines, are its abilities to induce T helper 1 (Th1) and CTL responses, the prolonged antigen expression, and the potential long-lived effector activity. Although it is well documented that direct injection of naked DNA encoding different antigens of viral, bacterial, parasitic, and tumor origin can elicit both humoral and cellular immune responses in various animal models, recent results from clinical trials suggest that the immunogenicity of DNA vaccine in humans may be limited. Recently, the use of naked DNA plasmids and recombinant attenuated viruses, such as adenovirus, vaccinia virus and Sindbis virus (Caulfield, et al., J. Virol. 2002; 76:10038-10043; Tsuji et al., J. Virol. 1998; 72:6907-6910; Rodrigues, et al., J. Immunol. 1997; 158:1268-1274), in their single dose or in a priming-boosting strategy (Li et al., Proc. Natl. Acad. Sci. U SA. 1993; 90:5214-5218; Amara et al., J. Virol. 2002; 76:7625-7631) have been proven to be potent inducers of a pathogen-specific CD8+ T-cell response in animal models. However, the use of recombinant viral vaccines has many disadvantages for practical use in humans. A majority of people worldwide has pre-existing immunity to adenovirus and vaccinia virus that cause impaired immune responses to vaccines, and these viruses are prevalent among human populations. Moreover, the amounts that are required for DNA vaccines in humans are extremely high, i.e. five milligram per dose per person.
Taken together, optimal regimens to enhance the immunogenicity and decrease the required dose of DNA vaccines as well as various subunit vaccines still remain to be established.